Our laboratory studies the molecules that govern the often-connected processes of cell death and inflammation. These processes normally protect against microbial infection, and allow tissue repair. Loss of control of cell death and inflammation underpins diseases such as sepsis, arthritis and cancer. Our goal is to understand how cell death and inflammation are controlled.
To this end we have made fundamental discoveries into cell death drivers of inflammation in cancer and infections that have led to high impact papers on this theme (e.g. Immunity 2012; Cell 2014; Blood 2014; Nature Comms 2015 & 21; Nature Micro 2016 & 17; Cell Reports 2017 & 18; PNAS 2017; Nature Immunol 2019; J. Immunol 2019; Immunity 2022; EMBO J 2023).
In partnership with Mermaid Bio, these discoveries are now informing our efforts to therapeutically target relevant cell death and inflammatory molecules using recent advances in lipid nanoparticle, mRNA, and nanobody technologies.
Our lab’s vision is to make breakthrough discoveries into how cell death controls the inflammatory response, and then harness this knowledge to develop new therapies.
Our lab has defined the signaling pathways by which cell death regulates, and often drives, inflammasome-mediated immune responses, and has implicated these in relevant disease models. These have included studies related to bacterial infections (Nature Micro. 2106), gout (Journal of Immunology 2019), pathogen inflammatory responses (Cell Reports 2018; Nature Communications 2021), COVID-19 (Immunity 2022) and hereditary autoinflammatory diseases (Cell Reports 2017; EMBO J 2023). Our work has resulted in patents and collaborations with international biotechnology companies, such as Mermaid Bio GmbH and Tetralogic Pharmaceuticals.
Too much cell death has been implicated in many diseases, from autoinflammatory conditions, to infections and cancer. It is now recognised that there is often redundancy and cross-talk in the cell death machinery and, from a therapeutic perspective, several cell death pathways may need to be targeted at the same time. We are developing multi-functional mRNAs that will inhibit several cell death and inflammatory pathways, and intend to deliver these using lipid nanoparticles to treat relevant conditions.
Team members: Dr Deepagan Gopal (and in collaboration with Mermaid Bio. GmbH).
Hepatocellular carcinoma (HCC) represents 85% of liver cancers, is the sixth most common cancer and, globally, is the fourth leading cause of cancer deaths. This project makes use of our cell death and inflammation deficient animals to study the molecular players that promote or inhibit HCC, using a HCC model driven by genetic mutations that cause liver cancer in humans.
Team members: Dr Deepagan Gopal
Cytosolic inflammasome protein complexes drive cell death and inflammation, and while they are key for innate immunity against pathogen infections, their excess activation causes a variety of autoinflammatory conditions. We recently defined a key post-translational modification of the inflammasome-associated cytokine IL-1beta (Nature Communications 2021). This project uses a CRISPR screen to identify the enzymes responsible for IL-1beta modification and will examine their function in inflamamsome-driven disease models. This project may uncover new targets for manipulating inflammasome activity for therapeutic benefit.
Team members: Ashley Weir
Cytokine shock syndromes are frequently lethal conditions often triggered by infectious pathogens in genetically susceptible people (e.g. sepsis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome). We have developed models of cytokine shock syndromes to identify the critical cell death and inflammatory pathways involved, and are using biochemical experiments and genetic manipulation (e.g. cell type-specific targeting) in order to define new therapeutic targets. Potential targets will be tested using new nanobody approaches and, in collaboration with industry, small molecule inhibitors.
Team Members: Farzaneh Shojaee
Host and microbial molecules both contribute to inflammatory bowel disease (IBD). This project examines how the combined actions of inflammatory cytokines and pathogen ligands can combine to cause pathological cell death in IBD using human intestinal organoid models. Using a variety of genetic (CRISPR/Cas9) and pharmacological approaches we are mapping the relevant cell death pathways identified via biochemical and genome-wide transcriptional profiling, and are translating these in vivo using relevant animal models.
Team Members: Jiyi Pang
We strive to create an inclusive and collaborative lab environment where everyone, from undergraduate students to senior post-docs, has the freedom to ask questions and pursue the science they are passionate about.
Past members of our lab include undergraduate students who have gone on to undertake PhDs or teaching positions, PhD students who have completed post-docs abroad at world-leading institutes, and post-docs who have gone on to start their own laboratories or pursue careers in clinical practice.
We aim to perform the best science possible by forming deep collaborations with other groups with diverse expertise. These include labs within WEHI, such as those led by James Murphy, Edwin Hawkins, Ian Wicks, Rebecca Feltham, Joanna Groom, Sandra Nicholson, John Silke and Seth Masters (WEHI) and laboratories outside of WEHI from Monash Univeristy (Thomas Naderer, Ana Traven), The Hudson Institute (Kate Lawlor, Jaclyn Pearson), the Olivia Newton John Research Centre (Marco Herold), Tel Aviv University (Motti Gerlic), Freiberg University (Olaf Gross) and the Technical University of Munich (Monica Yabal).
In addition, studies are often conducted with biotech companies, such as Mermaid Bio., GSK and Tetralogic Pharmaceuticals, where we aim to exploit our discoveries through the application of new therapeutic molecules.